RESUMO
Paclitaxel is one of the first-line treatments for breast, ovarian, and lung cancers. However, its use is limited by the high frequency of hypersensitivity reactions. In this retrospective chart review at Memorial Sloan Kettering Cancer Center, we assess clinical factors associated with immediate and delayed hypersensitivity reactions to paclitaxel and characterize delayed hypersensitivity reactions to paclitaxel in patients with breast cancer. 12,274 patients were treated with paclitaxel. 6,165 had breast cancer and 1,233 were seen by a dermatologist. 734 patients (11.9%) developed an immediate hypersensitivity reaction. Age (p < 0.001), race (p < 0.001), and prior history of allergy (p = 0.05) were associated with immediate hypersensitivity reactions. 147 patients (4.0%) had a rash of interest. The most common phenotypes were maculopapular (52%) and urticaria (36%). Race (p < 0.001) and history of allergy (p < 0.001) were associated with development of a cutaneous reaction. Patients with an immediate hypersensitivity reaction were more likely to have developed a delayed cutaneous reaction (OR = 1.80). Risk factors for development of immediate hypersensitivity reactions in this study were younger age, race, and history of allergy. Patients who developed an immediate hypersensitivity reaction were more likely to develop a delayed hypersensitivity reaction. Risk factors for development of the rash included Asian race and history of allergy. Identification of risk factors is critical to guide care coordination. Awareness of these clinical factors which are associated with development of a rash could guide providers in choosing treatment with paclitaxel or nab-paclitaxel. If the cutaneous reactions are bothersome to the patient, the transition of treatment from paclitaxel to nab-paclitaxel may be warranted, or a consideration of re-challenge or desensitization may be discussed.
Assuntos
Neoplasias da Mama , Hipersensibilidade Tardia , Paclitaxel , Humanos , Paclitaxel/efeitos adversos , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto , Fatores de Risco , Idoso , Hipersensibilidade Tardia/diagnóstico , Hipersensibilidade Tardia/epidemiologia , Hipersensibilidade Tardia/induzido quimicamente , Hipersensibilidade Tardia/imunologia , Neoplasias da Mama/tratamento farmacológico , Hipersensibilidade Imediata/epidemiologia , Hipersensibilidade Imediata/induzido quimicamente , Hipersensibilidade Imediata/diagnóstico , Hipersensibilidade Imediata/imunologia , Toxidermias/etiologia , Toxidermias/imunologia , Toxidermias/epidemiologia , Toxidermias/diagnóstico , Antineoplásicos Fitogênicos/efeitos adversos , Hipersensibilidade a Drogas/epidemiologia , Hipersensibilidade a Drogas/diagnóstico , Hipersensibilidade a Drogas/etiologia , Fatores EtáriosRESUMO
INTRODUCTION: Breast cancer is the most diagnosed tumor and a leading cause of cancer death in women worldwide. Taxanes are the most used chemotherapeutic agents and are strictly connected to neurotoxicity. Taxane-induced neuropathy (TIN) significantly impacts patients' quality of life (QOL). Early identification and management of TIN could improve preventive strategies to preserve patients' QOL during and after breast cancer treatment. OBJECTIVE: This prospective, observational study aimed to evaluate the taxane-induced neuropathy (TIN) in early breast cancer patients treated with weekly paclitaxel at an earlier stage and identify any correlation between TIN and QOL. METHODS: Data from stage I-III breast cancer patients treated with taxane-based therapy between 2018 and 2022 were collected at the Medical Oncology Unit of the University Hospital of Cagliari. Peripheral neuropathy was evaluated using the NCI-CTCAE scale (National Cancer Institute, Common Terminology Criteria for Adverse Events) at every drug administration. In contrast, QOL was assessed using EORTC QLC-CIPN20 and FACT-Taxane questionnaire at baseline (T0), after 4 weeks (T1) and 12 (T2) weeks of treatment. Statistical analysis was performed to evaluate the correlation between neurotoxicity and QOL. RESULTS: Neurotoxicity incidence peaked at the third, fourth, and sixth week of treatment, with patients reporting grade 1 and 2 neurotoxicity. Simultaneously with increasing doses of paclitaxel, significant differences in QOL were observed in early treatment cycles relating to TIN presentation. Patients with higher neurotoxicity grades reported lower QOL scores. CONCLUSIONS: Despite the absence of effective treatments to prevent paclitaxel-induced neurotoxicity, symptoms are managed through dosage reduction, delay, or treatment interruption. Future research should focus on identifying neuroprotective measures to avoid an irreversible decline in the quality of life for breast cancer survivors.
Assuntos
Neoplasias da Mama , Síndromes Neurotóxicas , Paclitaxel , Doenças do Sistema Nervoso Periférico , Qualidade de Vida , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Pessoa de Meia-Idade , Estudos Prospectivos , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/prevenção & controle , Paclitaxel/efeitos adversos , Paclitaxel/administração & dosagem , Idoso , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Adulto , Taxoides/efeitos adversos , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/administração & dosagem , Hidrocarbonetos Aromáticos com Pontes/efeitos adversos , Hidrocarbonetos Aromáticos com Pontes/uso terapêuticoRESUMO
OBJECTIVE: Chemotherapy during pregnancy has a certain risk of causing a series of complications, such as miscarriage, premature birth, or fetal growth restriction, although the relationship between these complications and chemotherapy is currently unclear. This experiment focuses on the possible damage mechanism of the chemotherapeutic drug paclitaxel on placental trophoblast cells, and explores whether chemotherapy can affect pregnancy outcomes by directly damaging placental tissue. METHODS: This study explored the mechanism of paclitaxel induced damage on placental trophoblast cell lines JEG-3 and BEWO through immunofluorescence staining, Western blot experiments, cell flow cytometry, Seahorese cell metabolism experiments, and mouse modeling verification. RESULTS: The experiment found that paclitaxel could induce JEG-3 and BEWO cells to produce reactive oxygen species (ROS), and elevate the ratio of Bax/Bcl-2 expression. Besides, paclitaxel mediated the reduction of mitochondrial membrane potential in JEG-3 and BEWO cells, causing damage and leading to mitochondrial autophagy and the occurrence of unfolded protein response. Paclitaxel inhibited the glycolysis rate of JEG-3 and BEWO cells, and leaded to impaired mitochondrial function, including decreased basal respiratory values, decreased respiratory reserve capacity, and proton leakage. In pregnant mice with tumor modeling, paclitaxel could cause DNA damage in placental tissue cells, and might lead to apoptosis of chemotherapy mice placental tissue cells and impairment of normal physiological functions. CONCLUSION: Paclitaxel may directly or indirectly affect the normal physiological functions of placental trophoblast cells, including energy metabolism and protein synthesis dysfunction, which may be related to the adverse pregnancy outcomes caused by paclitaxel chemotherapy.
Assuntos
Antineoplásicos Fitogênicos , Paclitaxel , Placenta , Espécies Reativas de Oxigênio , Trofoblastos , Paclitaxel/efeitos adversos , Paclitaxel/farmacologia , Feminino , Trofoblastos/efeitos dos fármacos , Trofoblastos/metabolismo , Gravidez , Animais , Camundongos , Humanos , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/farmacologia , Placenta/efeitos dos fármacos , Placenta/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Apoptose/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Linhagem Celular Tumoral , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Autofagia/efeitos dos fármacos , Linhagem CelularRESUMO
PURPOSE: Paclitaxel is effective chemotherapy against various cancers but can cause hypersensitivity reaction (HSR). This study aimed to identify predictors associated with paclitaxel HSR and develop a clinical prediction model to guide clinical decisions. METHODS: Data were collected from the medical records database of Rajavithi Hospital. Patients with cancer treated with paclitaxel from 2015 to 2022 were included, and a multivariable logistic regression analysis identified predictors associated with paclitaxel HSR. The scoring system was transformed and calibrated on the basis of diagnostic parameters. Discrimination and calibration performances were assessed. Internal validation was conducted using bootstrap resampling with 1,000 replications. RESULTS: This study involved 3,708 patients with cancer, with an incidence of paclitaxel HSR of 10.11%. An 11-predictor-based Pac-HSR scoring system was developed, involving the following factors: younger age; poor Eastern Cooperative Oncology Group performance status; previous history of paclitaxel HSR; medication allergy history; chronic obstructive airway disease; lung and cervical cancers; high actual dose of paclitaxel; no diphenhydramine premedication; low hemoglobin level; high WBC count; and high absolute lymphocyte count. The C-statistics was 0.73 (95% CI, 0.70 to 0.76), indicating acceptable discrimination. The P value of the Hosmer-Lemeshow goodness-of-fit test was 0.751. The ratio of observed and expected values was 1.00, indicating good calibration. At a cutoff point of 8, specificity was 75.28% and sensitivity was 57.07%. Internal validation indicated good performance with minimal bias, and decision curve analysis demonstrated improved prediction with the use of this scoring system in clinical decision making. CONCLUSION: This study developed the 11-predictor-based Pac-HSR scoring system for predicting paclitaxel HSR in patients with cancer. High-risk patients identified by this score should be prioritized for close monitoring and early treatment prophylaxis.
Assuntos
Hipersensibilidade a Drogas , Neoplasias , Paclitaxel , Humanos , Paclitaxel/efeitos adversos , Feminino , Masculino , Pessoa de Meia-Idade , Hipersensibilidade a Drogas/diagnóstico , Hipersensibilidade a Drogas/epidemiologia , Hipersensibilidade a Drogas/etiologia , Neoplasias/tratamento farmacológico , Idoso , Antineoplásicos Fitogênicos/efeitos adversos , Adulto , Estudos RetrospectivosRESUMO
Paclitaxel is a chemotherapy drug widely used for the treatment of various cancers based on its ability to potently stabilize cellular microtubules and block division in cancer cells. Paclitaxel-based treatment, however, accumulates in peripheral system sensory neurons and leads to a high incidence rate (over 50%) of chemotherapy induced peripheral neuropathy in patients. Using an established preclinical model of paclitaxel-induced peripheral neuropathy (PIPN), we examined proteomic changes in dorsal root ganglia (DRG) of adult male mice that were treated with paclitaxel (8 mg/kg, at 4 injections every other day) relative to vehicle-treated mice. High throughput proteomics based on liquid chromatography electrospray ionization mass spectrometry identified 165 significantly altered proteins in lumbar DRG. Gene ontology enrichment and bioinformatic analysis revealed an effect of paclitaxel on pathways for mitochondrial regulation, axonal function, and inflammatory purinergic signaling as well as microtubule activity. These findings provide insight into molecular mechanisms that can contribute to PIPN in patients.
Assuntos
Modelos Animais de Doenças , Gânglios Espinais , Neuralgia , Paclitaxel , Proteômica , Animais , Paclitaxel/efeitos adversos , Paclitaxel/farmacologia , Gânglios Espinais/metabolismo , Gânglios Espinais/efeitos dos fármacos , Masculino , Camundongos , Proteômica/métodos , Neuralgia/induzido quimicamente , Neuralgia/metabolismo , Neuralgia/tratamento farmacológico , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/farmacologia , Camundongos Endogâmicos C57BLRESUMO
Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a serious therapy-limiting side effect of commonly used anticancer drugs. Previous studies suggest that lipids may play a role in CIPN. Therefore, the present study aimed to identify the particular types of lipids that are regulated as a consequence of paclitaxel administration and may be associated with the occurrence of post-therapeutic neuropathy. Methods: High-resolution mass spectrometry lipidomics was applied to quantify d=255 different lipid mediators in the blood of n=31 patients drawn before and after paclitaxel therapy for breast cancer treatment. A variety of supervised statistical and machine-learning methods was applied to identify lipids that were regulated during paclitaxel therapy or differed among patients with and without post-therapeutic neuropathy. Results: Twenty-seven lipids were identified that carried relevant information to train machine learning algorithms to identify, in new cases, whether a blood sample was drawn before or after paclitaxel therapy with a median balanced accuracy of up to 90%. One of the top hits, sphinganine-1-phosphate (SA1P), was found to induce calcium transients in sensory neurons via the transient receptor potential vanilloid 1 (TRPV1) channel and sphingosine-1-phosphate receptors.SA1P also showed different blood concentrations between patients with and without neuropathy. Conclusions: Present findings suggest a role for sphinganine-1-phosphate in paclitaxel-induced biological changes associated with neuropathic side effects. The identified SA1P, through its receptors, may provide a potential drug target for co-therapy with paclitaxel to reduce one of its major and therapy-limiting side effects. Funding: This work was supported by the Deutsche Forschungsgemeinschaft (German Research Foundation, DFG, Grants SFB1039 A09 and Z01) and by the Fraunhofer Foundation Project: Neuropathic Pain as well as the Fraunhofer Cluster of Excellence for Immune-Mediated Diseases (CIMD). This work was also supported by the Leistungszentrum Innovative Therapeutics (TheraNova) funded by the Fraunhofer Society and the Hessian Ministry of Science and Arts. Jörn Lötsch was supported by the Deutsche Forschungsgemeinschaft (DFG LO 612/16-1).
Assuntos
Aprendizado de Máquina , Paclitaxel , Doenças do Sistema Nervoso Periférico , Esfingolipídeos , Paclitaxel/efeitos adversos , Humanos , Esfingolipídeos/metabolismo , Esfingolipídeos/sangue , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Feminino , Neoplasias da Mama/tratamento farmacológico , Lipidômica , Pessoa de Meia-Idade , Antineoplásicos Fitogênicos/efeitos adversos , IdosoRESUMO
BACKGROUND: Approximately 70% of patients receiving neurotoxic chemotherapy (e.g., paclitaxel or vincristine) will develop chemotherapy-induced peripheral neuropathy. Despite the known negative effects of CIPN on physical functioning and chemotherapy dosing, little is known about how to prevent CIPN. The development of efficacious CIPN prevention interventions is hindered by the lack of knowledge surrounding CIPN mechanisms. Nicotinamide adenine dinucleotide (NAD+) and cyclic-adenosine diphosphate ribose (cADPR) are potential markers of axon degeneration following neurotoxic chemotherapy, however, such markers have been exclusively measured in preclinical models of chemotherapy-induced peripheral neuropathy (CIPN). The overall objective of this longitudinal, observational study was to determine the association between plasma NAD+, cADPR, and ADPR with CIPN severity in young adults receiving vincristine or paclitaxel. METHODS: Young adults (18-39 years old) beginning vincristine or paclitaxel were recruited from Dana-Farber Cancer Institute. Young adults completed the QLQ-CIPN20 sensory and motor subscales and provided a blood sample prior to starting chemotherapy (T1) and at increasing cumulative vincristine (T2: 3-5 mg, T3: 7-9 mg) and paclitaxel (T2: 300-500 mg/m2, T3: 700-900 mg/m2) dosages. NAD+, cADPR, and ADPR were quantified from plasma using mass spectrometry. Metabolite levels and QLQ-CIPN20 scores over time were compared using mixed-effects linear regression models and/or paired two-sample tests. RESULTS: Participants (N = 50) were mainly female (88%), white (80%), and receiving paclitaxel (78%). Sensory and motor CIPN severity increased from T1-T3 (p < 0.001). NAD+ (p = 0.28), cADPR (p = 0.62), and ADPR (p = 0.005) values decreased, while cADPR/NAD+ ratio increased from T1-T3 (p = 0.50). There were no statistically significant associations between NAD + and QLQ-CIPN20 scores over time. CONCLUSIONS: To our knowledge, this is the first study to measure plasma NAD+, cADPR, and ADPR among patients receiving neurotoxic chemotherapy. Although, no meaningful changes in NAD+, cADPR, or cADPR/NAD+ were observed among young adults receiving paclitaxel or vincristine. Future research in an adequately powered sample is needed to explore the clinical utility of biomarkers of axon degeneration among patients receiving neurotoxic chemotherapy to guide mechanistic research and novel CIPN treatments.
Assuntos
Paclitaxel , Doenças do Sistema Nervoso Periférico , Vincristina , Humanos , Vincristina/efeitos adversos , Feminino , Paclitaxel/efeitos adversos , Adulto , Masculino , Adulto Jovem , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/sangue , Adolescente , Axônios/efeitos dos fármacos , Axônios/patologia , Estudos Longitudinais , NAD/metabolismo , NAD/sangue , Biomarcadores/sangue , Antineoplásicos Fitogênicos/efeitos adversos , Degeneração Neural/induzido quimicamente , Degeneração Neural/patologia , Degeneração Neural/sangueRESUMO
BACKGROUND: Irinotecan administration can lead to severe delayed-onset diarrhea (SDOD) in clinical practice. Currently, there is no reliable surrogate predictor of intestinal exposure to SN-38 and subsequent diarrhea incidence. METHODS: The relationship between fecal 7-ethyl-10-hydroxycamptothecin (SN-38) content and SDOD was investigated in Fisher 344 rats using a novel spectrofluorimetric method. Additionally, a pharmacokinetic study of irinotecan was performed to evaluate the biodistribution of SN-38 to establish the relationship between tissue and fecal SN-38 exposure. RESULTS: The spectrofluorimetric method was successfully employed to measure fecal SN-38 and CPT-11 content from Day 3 to Day 6 post-irinotecan administration. Only fecal SN-38 content on Day 3 exhibited a significantly positive correlation with SDOD incidence on Days 4 and 5. A cutoff value of SN-38 ≥ 0.066 mg/g in feces was identified, predicting severe diarrhea incidence with 81% accuracy and 80% specificity. The positive correlation between fecal SN-38 content and SN-38 exposure in the ileum on Day 3 was also reflected in the changes of indicators during intestinal injury, such as prostaglandin E2 level and antioxidant activity. CONCLUSION: Fecal SN-38 content proves to be representative of intestinal exposure to SN-38, indicative of intestinal injury, and predictive of SDOD incidence in rats, while the spectrofluorimetric method demonstrates the translational potential.
Assuntos
Camptotecina , Diarreia , Fezes , Irinotecano , Ratos Endogâmicos F344 , Animais , Irinotecano/farmacocinética , Irinotecano/efeitos adversos , Diarreia/induzido quimicamente , Camptotecina/análogos & derivados , Camptotecina/farmacocinética , Camptotecina/análise , Camptotecina/efeitos adversos , Fezes/química , Masculino , Ratos , Espectrometria de Fluorescência/métodos , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/análise , Distribuição Tecidual , Mucosa Intestinal/metabolismoAssuntos
Antineoplásicos Fitogênicos , Neoplasias do Endométrio , Paclitaxel , Penfigoide Bolhoso , Humanos , Feminino , Penfigoide Bolhoso/induzido quimicamente , Penfigoide Bolhoso/tratamento farmacológico , Neoplasias do Endométrio/tratamento farmacológico , Paclitaxel/efeitos adversos , Paclitaxel/uso terapêutico , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/uso terapêutico , Idoso , Pessoa de Meia-IdadeRESUMO
Cancer is the leading cause of disease-related death among children. Vincristine (VCR), a key component of childhood cancer treatment protocols, is associated with the risk of peripheral neuropathy (PN), a condition that may be reversible upon drug discontinuation but can also leave lasting sequelae. Single nucleotide polymorphism (SNP) in genes involved in VCR pharmacokinetics and pharmacodynamics have been investigated in relation to an increased risk of PN. However, the results of these studies have been inconsistent. A retrospective cohort study was conducted to investigate the potential association of drug transporter genes from the ATP-binding cassette (ABC) family and the centrosomal protein 72 (CEP72) gene with the development of PN in 88 Caucasian children diagnosed with cancer and treated with VCR. Genotyping was performed using real-time PCR techniques for the following SNPs: ABCB1 rs1128503, ABCC1 rs246240, ABCC2 rs717620, and CEP72 rs924607. The results indicated that age at diagnosis (OR = 1.33; 95% CI = 1.07-1.75) and the ABCC1 rs246240 G allele (OR = 12.48; 95% CI = 2.26-100.42) were associated with vincristine-induced peripheral neuropathy (VIPN). No association was found between this toxicity and CEP72 rs924607. Our study provides insights that may contribute to optimizing childhood cancer therapy in the future by predicting the risk of VIPN.
Assuntos
Proteína 2 Associada à Farmacorresistência Múltipla , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Neoplasias , Doenças do Sistema Nervoso Periférico , Polimorfismo de Nucleotídeo Único , Medicina de Precisão , Vincristina , Humanos , Vincristina/efeitos adversos , Vincristina/uso terapêutico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/genética , Criança , Feminino , Masculino , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Pré-Escolar , Medicina de Precisão/métodos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Adolescente , Estudos Retrospectivos , Proteínas de Ciclo Celular/genética , Lactente , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/uso terapêutico , Predisposição Genética para Doença , Genótipo , Alelos , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Proteínas Associadas aos MicrotúbulosRESUMO
BACKGROUND: Paclitaxel (PTX) is an essential cytotoxic anticancer agent and a standard treatment regimen component for various malignant tumors, including advanced unresectable non-small cell lung cancer, thymic cancer, and primary unknown cancers. However, chemotherapy-induced peripheral neuropathy (CIPN) caused by PTX is a significant adverse event that may lead to chemotherapy discontinuation and deterioration of the quality of life (QOL). Although treatment modalities such as goshajinkigan (GJG), pregabalin, and duloxetine are empirically utilized for CIPN, there is no established evidence for an agent as a preventive measure. We designed a randomized phase II trial (OLCSG2101) to investigate whether prophylactic GJG administration can prevent the onset of CIPN induced by PTX. METHODS: This study was designed as a two-arm, prospective, randomized, multicenter phase II trial. The patients will be randomly assigned to either the GJG prophylaxis arm (Arm A) or the GJG non-prophylaxis arm (Arm B), using cancer type (lung cancer or not) and age (<70 years or not) as adjustment factors. A total of 66 patients (33 in each arm) will be enrolled. DISCUSSION: The results of this study may contribute to better management of CIPN, which can enable the continuation of chemotherapy and maintenance of the patient's QOL. ETHICS AND DISSEMINATION: Ethical approval was obtained from the certified review board of Okayama University (approval no. CRB21-005) on September 28, 2021. Results will be published in peer-reviewed journals and presented at national and international conferences. TRIAL REGISTRATION: Japan Registry of Clinical Trials (registration number jRCTs061210047).
Assuntos
Medicamentos de Ervas Chinesas , Paclitaxel , Doenças do Sistema Nervoso Periférico , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/efeitos adversos , Ensaios Clínicos Fase II como Assunto , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Estudos Multicêntricos como Assunto , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/prevenção & controle , Estudos Prospectivos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is one of the major side effects and main reasons for affecting quality of life and dose reduction or even discontinuation of treatment in breast cancer patients. One of the most widely prescribed chemotherapies is the "taxanes." Considering that duloxetine has been used in treating neuropathies in recent years, this study aimed to investigate its effectiveness in preventing taxane-related neuropathy. MATERIAL AND METHODS: This is a randomized controlled trial on 47 patients: 24 received a placebo and 23 received duloxetine at 30 mg daily in the first week following the injection of paclitaxel and 60 mg during the second week in each chemotherapy cycle. Patients objective (nerve conduction velocity (NCV) values) and subjective symptoms (visual analog scale including; neuropathy, paresthesia, pain, cold sensitivity, and numbness), the grades of the patients' neuropathy (calculated according to Common Terminology Criteria for Adverse Events (CTCAE) v.5), and the presence of complications, before and after each chemotherapy cycle, were recorded. RESULTS: The placebo group experienced significantly higher occurrences of new neuropathy (8/23 in duloxetine vs 16/24 in placebo, P = 0.029) in NCV by tibial nerve latency (- 0.28% vs 19.87%, P = 0.006), tibial amplitude (4.40% vs - 10.88%, P = 0.049), and median nerve latency (8.72% vs 31.16%, P = 0.039); administration of duloxetine significantly reduced the scores of neuropathies (P < 0.001), pain (P = 0.027), during chemotherapy, and 6 weeks later; however, no significant effect was observed on paresthesia, numbness, cold sensitivity, and other NCV measurements. CONCLUSIONS: Paclitaxel can cause neuropathy, lasting for a long time. Our study showed duloxetine is potentially an effective medication that can prevent subjective and objective neuropathy.
Assuntos
Antineoplásicos Fitogênicos , Neoplasias da Mama , Cloridrato de Duloxetina , Paclitaxel , Doenças do Sistema Nervoso Periférico , Humanos , Cloridrato de Duloxetina/administração & dosagem , Cloridrato de Duloxetina/uso terapêutico , Paclitaxel/efeitos adversos , Paclitaxel/administração & dosagem , Feminino , Método Duplo-Cego , Neoplasias da Mama/tratamento farmacológico , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/prevenção & controle , Adulto , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/administração & dosagem , Qualidade de Vida , IdosoRESUMO
The low incidence of vincristine-induced peripheral neuropathy (VIPN) in Kenyan children may result from low vincristine exposure. We studied vincristine exposure in Kenyan children and dose-escalated in case of low vincristine exposure (NCT05844670). Average vincristine exposure was high. Individual vincristine exposure was assessed with a previously developed nomogram. A 20% dose increase was recommended for participants with low exposure and no VIPN, hyperbilirubinemia, or malnutrition. None of the 15 participants developed VIPN. Low vincristine exposure was seen in one participant: a dose increase was implemented without side effects. In conclusion, the participants did not develop VIPN despite having high vincristine exposure.
Assuntos
Estudos de Viabilidade , Doenças do Sistema Nervoso Periférico , Vincristina , Humanos , Vincristina/efeitos adversos , Vincristina/administração & dosagem , Feminino , Masculino , Quênia , Pré-Escolar , Criança , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Lactente , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/administração & dosagem , Neoplasias/tratamento farmacológico , Seguimentos , AdolescenteRESUMO
Vincristine (VCR) is one of the most widely used chemotherapy agents in treating pediatric cancer. Nonetheless, it is known to cause dose-dependent neurotoxicity which can impact virtually every organ system. Despite its widespread use, the precise impact of VCR on the lower urinary tract (LUT) remains inadequately elucidated. Our initial clinical and translational investigations suggest a sex-specific influence of childhood VCR exposure on LUT function. Thus, the current study aimed to investigate the late effects of systemic VCR exposure on LUT physiology and the underlying mechanisms, focusing on dosage and male-sex, employing juvenile CD-1 mice as a model. Male mice subjected to VCR exhibited augmented functional bladder capacity accompanied by frequent non-void contractions during awake cystometry, alongside mast cell accumulation within the bladder, compared to the saline-treated control group. Noteworthy functional changes were observed in bladder strips from the VCR group, including decreased nerve-mediated contraction, heightened contractile responses to cholinergic and purinergic agonists, enhanced responsiveness to histamine-primarily via histamine receptor 1 (Hrh1)-and an augmented relaxation effect with compound 48/80 (a mast cell degranulator), relative to the control group. Significant changes in gene expression levels associated with neuroinflammation and nociception were observed in both the bladder and lumbosacral dorsal root ganglia (Ls-DRG) of the VCR group. These findings suggest that VCR exposure during childhood, particularly in males, triggers neuroimmune responses in the bladder and Ls-DRG, amplifying responsiveness to neurotransmitters in the bladder, thereby contributing to LUT dysfunction characterized by a mixed bladder phenotype as a late effect during survivorship.
Assuntos
Bexiga Urinária , Vincristina , Animais , Masculino , Camundongos , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/patologia , Feminino , Vincristina/efeitos adversos , Vincristina/farmacologia , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Humanos , Fatores Sexuais , Relação Dose-Resposta a Droga , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/farmacologiaRESUMO
OBJECTIVES: To explore the experiences of utilising distal-extremity cryotherapy in reducing chemotherapy-induced peripheral neuropathy during Paclitaxel treatment on physical functioning, clinical and patient-reported outcomes, compared to standard care in people affected by breast cancer. METHODS: Four databases and one register were searched on 11 April 2023 to identify all relevant studies meeting the inclusion and exclusion criteria. These were CINAHL (via EBSCOhost), Cochrane Central Register of Controlled Trials, Medline (via EBSCOhost), Scopus, and Web of Science Core Collection, with no limiters placed on any of the searches. Additionally, relevant systematic reviews were scrutinised for potentially relevant studies for screening. RESULTS: Distal-extremity cryotherapy is a safe intervention with minimal risk for serious adverse events. However, insufficient data supports the mainstay clinical use of cryotherapy in reducing chemotherapy-induced peripheral neuropathy from Paclitaxel use within the breast cancer population. Heterogeneity in study design, cryotherapy mode, and measurement tools underscore the need for additional research. CONCLUSION: Despite limited data on the impact of distal-extremity cryotherapy in preventing chemotherapy-induced peripheral neuropathy, there are valuable implications for nursing practice arising from this review. IMPLICATIONS FOR NURSING PRACTICE: Nurses play a vital role in the clinical and experiential journey of people with breast cancer, it is important that they understand the available evidence and act as patient advocates. Assisting patients in understanding current research and encouraging participation in future studies, thereby enhancing our knowledge, and strengthening the available evidence base.
Assuntos
Neoplasias da Mama , Crioterapia , Paclitaxel , Doenças do Sistema Nervoso Periférico , Humanos , Paclitaxel/efeitos adversos , Paclitaxel/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Feminino , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/prevenção & controle , Crioterapia/métodos , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/uso terapêuticoRESUMO
BACKGROUND: Paclitaxel is a highly effective chemotherapeutic agent used to treat breast, ovarian, and other cancers. At the same time, paclitaxel causes peripheral neuropathy as a side effect in 45%-70% of patients. AIM: The aim of the study was to investigate the effect of paclitaxel-induced peripheral neuropathy on the development of pathological changes in the salivary glands of animals and to explore the possibility of correction of the identified changes with vitamin B/ATP complex. MATERIALS AND METHODS: To simulate toxic neuropathy, animals were injected i/p with paclitaxel 2 mg/kg for 4 days. In order to correct the identified changes, rats were injected i/m with vitamin B/ATP complex (1 mg/ kg) for 9 days. In the homogenate of the submandibular salivary glands, α-amylase activity, total proteolytic activity, total antitryptic activity, the content of medium mass molecules, thiobarbituric acid reactive substances (TBARS), oxidatively modified proteins, and catalase activity were determined. RESULTS: A significant increase in the content of oxidatively modified proteins, medium mass molecules, and the content of TBARS and significant decrease in the activity of catalase and amylase were determined in the salivary glands of animals with toxic neuropathy compared to these parameters in intact animals. Administration of vitamin B/ATP complex for 9 days against the background of paclitaxel-induced neuropathy led to normalization of antitryptic activity and amylase activity, a significant decrease in the content of oxidatively modified proteins, medium mass molecules, and TBARS along with a significant increase in catalase activity in the salivary glands of animals compared to the untreated rats with neuropathy. CONCLUSION: Paclitaxel-induced neuropathy caused the development of pathological changes in the salivary glands of rats, which was evidenced by a carbonyl- oxidative stress and impaired protein synthetic function. The correction with vitamin B/ATP complex restored the protein-synthetic function and the proteinase-inhibitor balance, suppressed the oxidative stress and normalized free radical processes in the salivary glands of rats.
Assuntos
Paclitaxel , Doenças do Sistema Nervoso Periférico , Glândulas Salivares , Animais , Paclitaxel/efeitos adversos , Paclitaxel/farmacologia , Glândulas Salivares/efeitos dos fármacos , Glândulas Salivares/patologia , Glândulas Salivares/metabolismo , Ratos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/patologia , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/farmacologia , Ratos Wistar , Estresse Oxidativo/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Complexo Vitamínico B/farmacologia , Complexo Vitamínico B/uso terapêutico , Masculino , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Catalase/metabolismoRESUMO
ABSTRACT: Paclitaxel-induced peripheral neurotoxicity (PIPN) is a potentially dose-limiting side effect in anticancer chemotherapy. Several animal models of PIPN exist, but their results are sometimes difficult to be translated into the clinical setting. We compared 2 widely used PIPN models characterized by marked differences in their methodologies. Female C57BL/6JOlaHsd mice were used, and they received only paclitaxel vehicle (n = 38) or paclitaxel via intravenous injection (n = 19, 70 mg/kg) once a week for 4 weeks (Study 1) or intraperitoneally (n = 19, 10 mg/kg) every 2 days for 7 times (Study 2). At the end of treatment and in the follow-up, mice underwent behavioral and neurophysiological assessments of PIPN. At the same time points, some mice were killed and dorsal root ganglia, skin, and sciatic and caudal nerve samples underwent pathological examination. Serum neurofilament light levels were also measured. The differences in the neurotoxicity parameters were analyzed using a nonparametric Mann-Whitney test, with significance level set at P < 0.05. Study 1 showed significant and consistent behavioral, neurophysiological, pathological, and serological changes induced by paclitaxel administration at the end of treatment, and most of these changes were still evident in the follow-up period. By contrast, study 2 evidenced only a transient small fiber neuropathy, associated with neuropathic pain. Our comparative study clearly distinguished a PIPN model recapitulating all the clinical features of the human condition and a model showing only small fiber neuropathy with neuropathic pain induced by paclitaxel.
Assuntos
Antineoplásicos Fitogênicos , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Paclitaxel , Doenças do Sistema Nervoso Periférico , Animais , Paclitaxel/toxicidade , Paclitaxel/efeitos adversos , Feminino , Camundongos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Antineoplásicos Fitogênicos/toxicidade , Antineoplásicos Fitogênicos/efeitos adversos , Humanos , Síndromes Neurotóxicas/etiologia , Gânglios Espinais/efeitos dos fármacos , Proteínas de Neurofilamentos/metabolismoRESUMO
This study aimed to investigate changes in hand sensation (finger tactile threshold and two-point discrimination) and function in patients with malignant lymphoma, particularly during the early stages of chemotherapy with vincristine. Eighteen patients with malignant lymphoma were enrolled in this study. Data on the Common Terminology Criteria for Adverse Events Version 4.0, the visual analog scale for hand numbness, the Semmes Weinstein monofilament test, static and moving two-point discrimination (2PD), grip strength, pinch strength, and the Purdue Pegboard test were collected at 3 time points: before the start of chemotherapy (T0), after the first cycle of chemotherapy (T1), and after the second cycle of chemotherapy (T2). No significant changes were observed in Semmes Weinstein monofilament test at T0, T1, or T2 in either hand. However, the static 2PD was significantly worse for the right ring, little, and left middle fingers, whereas the moving 2PD was significantly worse for the right ring, left index, middle, and ring fingers. Furthermore, the visual analog scale scores for hand numbness and left-hand grip strength worsened significantly. Right-hand grip strength, pinch strength of both hands, and Purdue Pegboard test showed no significant deterioration. Chemotherapy with vincristine may affect hand sensation and function in patients with malignant lymphoma by exacerbating finger 2PD and hand numbness. Additionally, during the early stages of vincristine chemotherapy, it is important to monitor for a decrease in grip strength specifically in the left hand.
Assuntos
Força da Mão , Mãos , Linfoma , Vincristina , Humanos , Vincristina/efeitos adversos , Vincristina/administração & dosagem , Masculino , Feminino , Pessoa de Meia-Idade , Linfoma/tratamento farmacológico , Idoso , Adulto , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/administração & dosagem , Hipestesia/induzido quimicamenteRESUMO
BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a treatment-limiting and debilitating neurotoxicity of many commonly used anti-cancer agents, including paclitaxel. The objective of this study was to confirm the previously found inverse association between pre-treatment blood concentrations of histidine and CIPN occurrence and examine relationships of other amino acids with CIPN severity. METHODS: Pre-treatment serum concentrations of 20 amino acids were measured in the SWOG S0221 (NCT00070564) trial of patients with early-stage breast cancer receiving paclitaxel. The associations between amino acids and CIPN severity were tested in regression analysis adjusted for paclitaxel schedule, age, self-reported race, and body mass index with Bonferroni correction. The network of metabolic pathways of amino acids was analyzed using over-representation analysis. The partial correlation network of amino acids was evaluated using a debiased sparse partial correlation algorithm. RESULTS: In the primary analysis, histidine concentration was not associated with CIPN occurrence (odds ratio (OR) = 0.97 [0.83, 1.13], p = 0.72). In secondary analyses, higher concentrations of four amino acids, glutamate (ß = 0.58 [0.23, 0.93], p = 0.001), phenylalanine (ß = 0.54 [0.19, 0.89], p = 0.002), tyrosine (ß = 0.57 [0.23, 0.91], p = 0.001), and valine (ß = 0.58 [0.24, 0.92], p = 0.001) were associated with more severe CIPN, but none of these associations retained significance after adjustment. In the over-representation analysis, no amino acid metabolic pathways were significantly enriched (all FDR > 0.05). In the network of enriched pathways, glutamate metabolism had the highest centrality. CONCLUSIONS: This analysis showed that pre-treatment serum amino acid concentrations are not strongly predictive of CIPN severity. Prospectively designed studies that assess non-amino acid metabolomics predictors are encouraged.